Investigational New Drugs 9: 253-256, 1991. 9 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Phase II trial of daily oral etoposide in patients with advanced non-small cell lung cancer Scott Saxman 1, Patrick J. Loehrer, Sr. 1, Keith Logie2, Doyle Stephens 3, Frank Workman 4, Daniel Scullin 5, Lawrence H. Einhorn 5 and Rafat Ansari 6
1Indiana University, Department of Medicine, Indianapolis, IN; 20ncology & Hematology Associates, Inc., Indianapolis, IN," 3Medical Oncology Consultants, Muncie, IN; 4Memorial Clinic of Indianapolis, Indianapolis, IN," 5Dobbs, Grimaldi, Seultin & Dannaher, Louisville, KY; 6Michiana HematologyOncology, P.C., South Bend, IN, USA (from the Hoosier Oncology Group, the Walther Cancer Institute, Indianapofis, IN," Department of Medicine, Indiana University, Indianapolis, IN, USA
Key words: lung cancer, etoposide Abstract
Forty-six previously untreated patients with advanced non-small cell lung cancer (NSCLC) were entered into a Hoosier Oncology Group phase II trialof daily oral etoposide 50 mg/m2/d. The dose limiting toxicity was granulocytopenia. The non-hematologic toxicity was mild, with only 19% of patients developing Grade 3 or 4 leukopenia. Two partial responses of 10 and 16 weeks duration were seen in 43 evaluable patients, for an overall response rate of 4%. We conclude that daily oral etoposide has minimal activity in advanced NSCLC, and does not improve response rates over conventional 1-5 day intravenous etoposide administration.
Lung cancer is the leading cause of cancer related death in the United States. Approximately 110,000 new cases of non-small cell lung (NSCLC) are diagnosed annually with the majority of patients presenting with advanced disease. Although response rates of up to 40~ have been reported with combination chemotherapy regimens, the impact of these therapies on survival in patients with advanced disease has been minimal at best. Etoposide is a widely used chemotherapeutic drug in clinical oncology with activity in germ cell malignancies, small cell lung cancer, lymphomas and leukemias [1-5]. The major dose-limiting toxicity of etoposide is myelosuppression. In NSCLC, etoposide has reported response rates between 4~ and 30~ as a single agent [6,7]. Furthermore, etoposide has also been used in many combination chemotherapy regimens for NSCLC. Recently, Slevin et al. demonstrated the impor-
tance of schedule dependency of etoposide. An improved response rate and duration of response were seen in patients with small cell lung cancer when etoposide was administered daily for 5 days, versus the identical total dosage administered on a single day [8]. The availability of oral etoposide makes it feasible to administer daily doses of this drug for longer periods o f time to allow further investigation. of the schedule dependency of this drug [9,10]. Phase I studies suggest that prolonged oral ad- , ministration of etoposide might enhance antitumor efficacy by exploiting the drug's schedule dependency [11]. Prolonged administration of low doses of etoposide has been investigated in small cell lung cancer [12] and in germ cell tumors [13]. These studies demonstrated that this method of administration was well tolerated with myelosuppression and alopecia being the predominant toxicities. In April 1989, the Hoosier Oncology Group
Dr. Einhorn is the Walther American Cancer Society Professor of Clinical Oncology.
254 (HOG) began a phase II study to evaluate the response rate, duration of remission and toxicity o f oral etoposide administered in a daily oral dosage for the treatment of patients with NSCLC.
Patients and methods From May, 1989 through October, 1989 46 consecutive patients with a histologic diagnosis of metastatic or locally unresectable NSCLC were entered into this H O G study. Stage III patients deemed non-operable because of concurrent medical illnesses or who progressed after radiation therapy were eligible as were patients who recurred with their disease after surgical resection. All patients had measurable or evaluable disease. Patients with a history of previous chemotherapy, or concurrent radiotherapy were not eligible. Other eligibility criteria were Karnofsky performance status (KPS) of 50 or greater, serum bilirubin less than 2 mg/dl, serum creatinine less than 2.0 mg/dl, white blood cell count above 3000/m ~, platelet count greater than 100,000/ram 3, and a life expectancy of 4 weeks or more. Written informed consent was required and obtained in all cases. Etoposide was given in a daily oral dose of 50 m g / m 2 for 21 days followed by 7 days off therapy (one cycle). Since oral etoposide is marketed only in a 50 mg capsule, the dose was rounded to the nearest 25 mg and if necessary given in alternating dosages: e.g., if the calculated daily dose was 75 rag, the patient was given alternating daily dosages of 50 rag-100 m g - 5 0 rag, etc. Pretreatment evaluation included history and physical examination, complete blood cell (CBC) count, sequential multiple analysis biochemical profile (SMA-12), posteroanterior (PA) and lateral chest x-ray, and computerized tomography (CT) of the liver and adrenal glands. CBC's were repeated once a week during the first 8 weeks of study, and at least every 4 weeks subsequently. SMA-12, tumor measurements, and PA and lateral chest x-rays were performed every 4 weeks during the study. CT scans were repeated as indicated to demonstrate response. Etoposide was temporarily discontinued for 1
week if in the first 8 weeks of therapy during weekly CBC's the granulocyte count was less than 500/mm 3 a n d / o r the platelet count was less than 50,000/ mm 3. Therapy was resumed with a 25% dose reduction if the granulocyte count recovered to greater than 1500/ram 3, and the platelet count to greater than 75,000/ram 3. If at the start of a course of therapy the platelet count was less than 50,000/ mm 3 a n d / o r the granulocyte count was less than 500/ram 3, therapy was delayed for one week and then resumed without a dosage reduction if recovery of blood counts above these levels had been achieved. The dose was also reduced by 25% if any episode of granulocytopenic fever or a need for platelet transfusion occurred. No patient was allowed more than a 25~ dose reduction during any individual course. There was no dose escalation. Median survival was calculated according to the Kaplan-Meier method [14]. Survival and response durations were calculated from the start of etoposide and the date remission was first achieved. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of diameters of measurable lesions for at least one month. A complete remission (CR) was defined as the complete disappearance of all objective disease for at least one month. Progression was indicated by the development of new lesions or an increase of 25% or more in the sum of the products of diameters of measurable lesions.
Results Of the 46 patients who entered the study, 43 were evaluable. Three patients refused treatment after registration and are not included in this analysis. Patient characteristics are summarized in Table 1.
Toxicity The main dose-limiting toxicity was myelosuppression, especially granulocytopenia. Five patients (12%) developed Eastern Cooperative Oncology Group (ECOG) grade 4 leukopenia (granulocytes < 500/ram3), and 3 patients (7%) developed grade
255 Table 1. Patient characteristics
Characteristics
Number
No. patients entered 46 No. patients evaluable 43 (93%) Male (~ 36 (84%) Female (070) 7 (16o70) Median performance status (range) 80 (50- 100) Median age in years (range) 62 (45- 82) Prior radiation therapy 14 (33~ Prior thoracic surgery 1 (2O7o) Sites of disease* Lung 39 (91O7o) Cervical/supraclavicularlymph nodes 8 (19~ Liver 6 (14%) Adrenal 6 (14O7o) Bone 8 (19%) * Number adds up to more than 43 due to patients with multiple sites of disease. Histology Squamous cell (%) 10 (23%) Adenocarcinoma (%) 16 (37%) Undifferentiated large cell (%) 12 (28%) Mixed histology (%) 5 (12~
3 leukopenia (granulocytes 500-1000/mm3). Of these 8 patients, 4 (50%) had received prior radiation therapy. Only 2 patients (5%) developed granulocytopenic infections. Thrombocytopenia was mild with only 2 patients developing grade 2 thrombocytopenia (platelets > 50,000 < 90,000/mm3). The relationship of anemia to daily oral etoposide was difficult to assess because many patients presented with chronic anemia associated with malignancy, however 3 patients (7%) developed anemia severe enough to require packed red cell transfusion. The only drug related death was in a patient who died of pneumonia but was discovered to have surreptitiously continued to take oral etoposide after developing granulocytopenia. Nonhematologic toxicity was generally mild with 20 patients (47%) developing alopecia, 14 patients (33%) developing mild nausea or vomiting, and 7 patients (16%)having stomatitis.
achieving a CR. One of these patients had a > 50% reduction in a supraclavicular lymph node, and the other had a > 75% reduction in liver metastasis. The duration of the PRs was 10 weeks and 16 weeks, with survival being 18 and 24 weeks respectively. One of these patients died of progressive disease, and the other died of acute nonlymphocytic leukemia which developed 3 months after the etoposide was discontinued. Median survival for the entire patient population was 26 weeks (95% C I = 2 1 to 27 weeks) [15].
Discussion Previous phase II trials of etoposide as a single agent in NSCLC have yielded mixed results. Anderson et al. [6] treated 82 patients with oral etoposide 100 mg BID for 5 days and reported a 30% overall response rate. Investigators at Memorial SloanKettering Cancer Center treated 51 patients with intravenous etoposide on days 1, 3, 5 o f a 21 day cycle with overall response rates of only 4% [7]. In this study, however, 50% o f the patients had received prior chemotherapy. The purpose of this H O G trial was to determine whether prolonged administration of etoposide in oral form improved the response rates over conventional 1 - 5 day intravenous dosing schedules in previously untreated patients. Although there was acceptable toxicity with only 19% of patients developing Grade 3 or 4 leukopenia, single agent etoposide given in this fashion in our trial had minimal activity with only 2 patients achieving a PR, and no complete responders. We conclude that oral etoposide has only minimal activity in NSCLC when given on a 21 day schedule.
Acknowledgements The authors express gratitude to Mike Miller, Ph.D., and Lori Kalasinski, M . P . H .
Responses and survival
References
Two of the 43 evaluable patients (5%, 95%, CI = 1% to 16~ had an objective PR with no patients
1. Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ: Disseminated germ cell tumors: Chemotherapy
256
2.
3.
4.
5.
6.
7.
8.
with cisplatin plus bleomycin plus either vinblastine or etoposide. NEJM 316:1435-1440, 1987 Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G: VP-16 and cisplatin as first-line therapy of small-cell lung cancer. J Clin Oncol 3:1471-1477, 1985 Bender RA, Anderson T, Fisher RI, Young RC: Activity of the epipodophyllotoxin VP-16 in the treatment of combination chemotherapy-resistant non-Hodgkin's lymphoma. Am J Hematol 5:203-209, 1978 McElwain T J, Selby P: Etoposide in combination for the treatment of Hodgkin's disease. In: Issell BF, Muggia FM, Carter SK (eds) Etoposide: Current Status and New Developments. Orlando: Academic Press, .Inc., 1984, pp 293-299 Bennett JM, Lymann GH, Cassileth PA, Glick JH, Oken MM: A phase II trial of VP-16-213 in adults with refractory acute myeloid leukemia: An Eastern Cooperative Oncology Group study. Am J Clin Oncol 7:471-473, 1984 Anderson G, Peel ET, Cheong CMB, Broderick N J: Etoposide - An effective single drug for treating bronchogenic carcinoma. J Clin Oncol 8:215-218, 1982 Chapman R, Itri L, Gralla R, Kelsen D, Casper E, Golbey R: Phase II trial of VP-16-213 in non-small cell lung cancer. Cancer Chemother Pharm 7:205-207, 1982 Slevin ML, Clark PI, Osborne R J, et al.: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. (Abstract) Proc Am Soc Clin Oncol 5:175, 1986
9. Stewart DJ, Nundy D, Maroun JA, Tetreault L, Prior J: Bioavailability, pharmacokinetics and clinical effects of an oral preparation of etoposide. Cancer Treat Rep 69:269-273, 1985 10. Cavalli F, Sonntag RW, Jungi F, Senn HS, Brunner KW: VP-16-213 monotherapy for remission induction of small cell lung cancer: A randomized trial using dosage schedules. Cancer Treat Rep 62:473-475, 1978 11. Hainsworth JD, Johnson DH, Frazier SR, Greco FA: Chronic daily administration of oral etoposide - a phase I trial. J Clin Oncol 7:396-401, 1989 12. Einhorn LH, Pennington K, McClean J: Phase II trial of daily oral VP-16 in refractory small cell lung cancer: A Hoosier Oncology Group study. Semin Oncol 17:32-35, 1990 (suppl 2) 13. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17:36-39, 1990 (suppl 2) 14. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1981 15. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-41, 1982
Address for offprints: S. Saxman, Indiana University Medical Center, University Hospital - A109, 926 W. Michigan, Indianapolis, IN 46202, USA
Phase II trial of daily oral etoposide in patients with advanced non-small cell lung cancer Scott Saxman 1, Patrick J. Loehrer, Sr. 1, Keith Logie2, Doyle Stephens 3, Frank Workman 4, Daniel Scullin 5, Lawrence H. Einhorn 5 and Rafat Ansari 6
1Indiana University, Department of Medicine, Indianapolis, IN; 20ncology & Hematology Associates, Inc., Indianapolis, IN," 3Medical Oncology Consultants, Muncie, IN; 4Memorial Clinic of Indianapolis, Indianapolis, IN," 5Dobbs, Grimaldi, Seultin & Dannaher, Louisville, KY; 6Michiana HematologyOncology, P.C., South Bend, IN, USA (from the Hoosier Oncology Group, the Walther Cancer Institute, Indianapofis, IN," Department of Medicine, Indiana University, Indianapolis, IN, USA
Key words: lung cancer, etoposide Abstract
Forty-six previously untreated patients with advanced non-small cell lung cancer (NSCLC) were entered into a Hoosier Oncology Group phase II trialof daily oral etoposide 50 mg/m2/d. The dose limiting toxicity was granulocytopenia. The non-hematologic toxicity was mild, with only 19% of patients developing Grade 3 or 4 leukopenia. Two partial responses of 10 and 16 weeks duration were seen in 43 evaluable patients, for an overall response rate of 4%. We conclude that daily oral etoposide has minimal activity in advanced NSCLC, and does not improve response rates over conventional 1-5 day intravenous etoposide administration.
Lung cancer is the leading cause of cancer related death in the United States. Approximately 110,000 new cases of non-small cell lung (NSCLC) are diagnosed annually with the majority of patients presenting with advanced disease. Although response rates of up to 40~ have been reported with combination chemotherapy regimens, the impact of these therapies on survival in patients with advanced disease has been minimal at best. Etoposide is a widely used chemotherapeutic drug in clinical oncology with activity in germ cell malignancies, small cell lung cancer, lymphomas and leukemias [1-5]. The major dose-limiting toxicity of etoposide is myelosuppression. In NSCLC, etoposide has reported response rates between 4~ and 30~ as a single agent [6,7]. Furthermore, etoposide has also been used in many combination chemotherapy regimens for NSCLC. Recently, Slevin et al. demonstrated the impor-
tance of schedule dependency of etoposide. An improved response rate and duration of response were seen in patients with small cell lung cancer when etoposide was administered daily for 5 days, versus the identical total dosage administered on a single day [8]. The availability of oral etoposide makes it feasible to administer daily doses of this drug for longer periods o f time to allow further investigation. of the schedule dependency of this drug [9,10]. Phase I studies suggest that prolonged oral ad- , ministration of etoposide might enhance antitumor efficacy by exploiting the drug's schedule dependency [11]. Prolonged administration of low doses of etoposide has been investigated in small cell lung cancer [12] and in germ cell tumors [13]. These studies demonstrated that this method of administration was well tolerated with myelosuppression and alopecia being the predominant toxicities. In April 1989, the Hoosier Oncology Group
Dr. Einhorn is the Walther American Cancer Society Professor of Clinical Oncology.
254 (HOG) began a phase II study to evaluate the response rate, duration of remission and toxicity o f oral etoposide administered in a daily oral dosage for the treatment of patients with NSCLC.
Patients and methods From May, 1989 through October, 1989 46 consecutive patients with a histologic diagnosis of metastatic or locally unresectable NSCLC were entered into this H O G study. Stage III patients deemed non-operable because of concurrent medical illnesses or who progressed after radiation therapy were eligible as were patients who recurred with their disease after surgical resection. All patients had measurable or evaluable disease. Patients with a history of previous chemotherapy, or concurrent radiotherapy were not eligible. Other eligibility criteria were Karnofsky performance status (KPS) of 50 or greater, serum bilirubin less than 2 mg/dl, serum creatinine less than 2.0 mg/dl, white blood cell count above 3000/m ~, platelet count greater than 100,000/ram 3, and a life expectancy of 4 weeks or more. Written informed consent was required and obtained in all cases. Etoposide was given in a daily oral dose of 50 m g / m 2 for 21 days followed by 7 days off therapy (one cycle). Since oral etoposide is marketed only in a 50 mg capsule, the dose was rounded to the nearest 25 mg and if necessary given in alternating dosages: e.g., if the calculated daily dose was 75 rag, the patient was given alternating daily dosages of 50 rag-100 m g - 5 0 rag, etc. Pretreatment evaluation included history and physical examination, complete blood cell (CBC) count, sequential multiple analysis biochemical profile (SMA-12), posteroanterior (PA) and lateral chest x-ray, and computerized tomography (CT) of the liver and adrenal glands. CBC's were repeated once a week during the first 8 weeks of study, and at least every 4 weeks subsequently. SMA-12, tumor measurements, and PA and lateral chest x-rays were performed every 4 weeks during the study. CT scans were repeated as indicated to demonstrate response. Etoposide was temporarily discontinued for 1
week if in the first 8 weeks of therapy during weekly CBC's the granulocyte count was less than 500/mm 3 a n d / o r the platelet count was less than 50,000/ mm 3. Therapy was resumed with a 25% dose reduction if the granulocyte count recovered to greater than 1500/ram 3, and the platelet count to greater than 75,000/ram 3. If at the start of a course of therapy the platelet count was less than 50,000/ mm 3 a n d / o r the granulocyte count was less than 500/ram 3, therapy was delayed for one week and then resumed without a dosage reduction if recovery of blood counts above these levels had been achieved. The dose was also reduced by 25% if any episode of granulocytopenic fever or a need for platelet transfusion occurred. No patient was allowed more than a 25~ dose reduction during any individual course. There was no dose escalation. Median survival was calculated according to the Kaplan-Meier method [14]. Survival and response durations were calculated from the start of etoposide and the date remission was first achieved. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of diameters of measurable lesions for at least one month. A complete remission (CR) was defined as the complete disappearance of all objective disease for at least one month. Progression was indicated by the development of new lesions or an increase of 25% or more in the sum of the products of diameters of measurable lesions.
Results Of the 46 patients who entered the study, 43 were evaluable. Three patients refused treatment after registration and are not included in this analysis. Patient characteristics are summarized in Table 1.
Toxicity The main dose-limiting toxicity was myelosuppression, especially granulocytopenia. Five patients (12%) developed Eastern Cooperative Oncology Group (ECOG) grade 4 leukopenia (granulocytes < 500/ram3), and 3 patients (7%) developed grade
255 Table 1. Patient characteristics
Characteristics
Number
No. patients entered 46 No. patients evaluable 43 (93%) Male (~ 36 (84%) Female (070) 7 (16o70) Median performance status (range) 80 (50- 100) Median age in years (range) 62 (45- 82) Prior radiation therapy 14 (33~ Prior thoracic surgery 1 (2O7o) Sites of disease* Lung 39 (91O7o) Cervical/supraclavicularlymph nodes 8 (19~ Liver 6 (14%) Adrenal 6 (14O7o) Bone 8 (19%) * Number adds up to more than 43 due to patients with multiple sites of disease. Histology Squamous cell (%) 10 (23%) Adenocarcinoma (%) 16 (37%) Undifferentiated large cell (%) 12 (28%) Mixed histology (%) 5 (12~
3 leukopenia (granulocytes 500-1000/mm3). Of these 8 patients, 4 (50%) had received prior radiation therapy. Only 2 patients (5%) developed granulocytopenic infections. Thrombocytopenia was mild with only 2 patients developing grade 2 thrombocytopenia (platelets > 50,000 < 90,000/mm3). The relationship of anemia to daily oral etoposide was difficult to assess because many patients presented with chronic anemia associated with malignancy, however 3 patients (7%) developed anemia severe enough to require packed red cell transfusion. The only drug related death was in a patient who died of pneumonia but was discovered to have surreptitiously continued to take oral etoposide after developing granulocytopenia. Nonhematologic toxicity was generally mild with 20 patients (47%) developing alopecia, 14 patients (33%) developing mild nausea or vomiting, and 7 patients (16%)having stomatitis.
achieving a CR. One of these patients had a > 50% reduction in a supraclavicular lymph node, and the other had a > 75% reduction in liver metastasis. The duration of the PRs was 10 weeks and 16 weeks, with survival being 18 and 24 weeks respectively. One of these patients died of progressive disease, and the other died of acute nonlymphocytic leukemia which developed 3 months after the etoposide was discontinued. Median survival for the entire patient population was 26 weeks (95% C I = 2 1 to 27 weeks) [15].
Discussion Previous phase II trials of etoposide as a single agent in NSCLC have yielded mixed results. Anderson et al. [6] treated 82 patients with oral etoposide 100 mg BID for 5 days and reported a 30% overall response rate. Investigators at Memorial SloanKettering Cancer Center treated 51 patients with intravenous etoposide on days 1, 3, 5 o f a 21 day cycle with overall response rates of only 4% [7]. In this study, however, 50% o f the patients had received prior chemotherapy. The purpose of this H O G trial was to determine whether prolonged administration of etoposide in oral form improved the response rates over conventional 1 - 5 day intravenous dosing schedules in previously untreated patients. Although there was acceptable toxicity with only 19% of patients developing Grade 3 or 4 leukopenia, single agent etoposide given in this fashion in our trial had minimal activity with only 2 patients achieving a PR, and no complete responders. We conclude that oral etoposide has only minimal activity in NSCLC when given on a 21 day schedule.
Acknowledgements The authors express gratitude to Mike Miller, Ph.D., and Lori Kalasinski, M . P . H .
Responses and survival
References
Two of the 43 evaluable patients (5%, 95%, CI = 1% to 16~ had an objective PR with no patients
1. Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ: Disseminated germ cell tumors: Chemotherapy
256
2.
3.
4.
5.
6.
7.
8.
with cisplatin plus bleomycin plus either vinblastine or etoposide. NEJM 316:1435-1440, 1987 Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G: VP-16 and cisplatin as first-line therapy of small-cell lung cancer. J Clin Oncol 3:1471-1477, 1985 Bender RA, Anderson T, Fisher RI, Young RC: Activity of the epipodophyllotoxin VP-16 in the treatment of combination chemotherapy-resistant non-Hodgkin's lymphoma. Am J Hematol 5:203-209, 1978 McElwain T J, Selby P: Etoposide in combination for the treatment of Hodgkin's disease. In: Issell BF, Muggia FM, Carter SK (eds) Etoposide: Current Status and New Developments. Orlando: Academic Press, .Inc., 1984, pp 293-299 Bennett JM, Lymann GH, Cassileth PA, Glick JH, Oken MM: A phase II trial of VP-16-213 in adults with refractory acute myeloid leukemia: An Eastern Cooperative Oncology Group study. Am J Clin Oncol 7:471-473, 1984 Anderson G, Peel ET, Cheong CMB, Broderick N J: Etoposide - An effective single drug for treating bronchogenic carcinoma. J Clin Oncol 8:215-218, 1982 Chapman R, Itri L, Gralla R, Kelsen D, Casper E, Golbey R: Phase II trial of VP-16-213 in non-small cell lung cancer. Cancer Chemother Pharm 7:205-207, 1982 Slevin ML, Clark PI, Osborne R J, et al.: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. (Abstract) Proc Am Soc Clin Oncol 5:175, 1986
9. Stewart DJ, Nundy D, Maroun JA, Tetreault L, Prior J: Bioavailability, pharmacokinetics and clinical effects of an oral preparation of etoposide. Cancer Treat Rep 69:269-273, 1985 10. Cavalli F, Sonntag RW, Jungi F, Senn HS, Brunner KW: VP-16-213 monotherapy for remission induction of small cell lung cancer: A randomized trial using dosage schedules. Cancer Treat Rep 62:473-475, 1978 11. Hainsworth JD, Johnson DH, Frazier SR, Greco FA: Chronic daily administration of oral etoposide - a phase I trial. J Clin Oncol 7:396-401, 1989 12. Einhorn LH, Pennington K, McClean J: Phase II trial of daily oral VP-16 in refractory small cell lung cancer: A Hoosier Oncology Group study. Semin Oncol 17:32-35, 1990 (suppl 2) 13. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17:36-39, 1990 (suppl 2) 14. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1981 15. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-41, 1982
Address for offprints: S. Saxman, Indiana University Medical Center, University Hospital - A109, 926 W. Michigan, Indianapolis, IN 46202, USA
